GLIAVAX: A stratified phase II clinical trial of avelumab and axitinib in patients with recurrent glioblastoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2034-2034 ◽  
Author(s):  
Bart Neyns ◽  
Laila Ben Salama ◽  
Gil Awada ◽  
Jennifer De Cremer ◽  
Julia Katharina Schwarze ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Single Agent ◽  
Recurrent Glioblastoma ◽  
Clinical Activity ◽  
Open Label ◽  
Grade 5 ◽  
Phase 2 Clinical Trial ◽  
Prior Surgery ◽  
Grade 3 ◽  
Tumor Types

2034 Background: Patients (pts) with recurrent glioblastoma (rGB) have a poor prognosis, and no treatment option demonstrated to improve survival in a randomized trial. Axitinib (AXI), an oral VEGFR 1-3 inhibitor has demonstrated single agent activity in rGB and reduces the need for corticosteroids (CS). Avelumab (AVE) is a fully human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types. Combination of AXI and AVE may improve the outcome of pts with rGB. Methods: This open-label, dual-strata, single-center phase 2 clinical trial investigated the activity of AXI plus AVE in adult pts with rGB following prior surgery, RT and temozolomide. Pts were stratified according to their baseline use of CS. Pts without baseline need for CS initiated treatment with AXI (5 mg oral BID) plus AVE (10 mg/kg IV Q2W) (cohort-1). Pts in need of CS initiated AXI as a monotherapy; AVE could be added to AXI after 6 wks if the CS dose could be tapered to a physiologic dose level or less (cohort-2). Six-month-PFS served as the primary endpoint (with a prespecified threshold of ≥ 50% for cohort-1) according to Fleming one-stage design. Results: Between Jun 2017 and Aug 2018, 54 pts (27 per cohort) were enrolled (med age 55 y [range 19-75]; 63% male; 91% WHO PS 0-1). All pts in cohort-1 and 16 pts (59%) in cohort-2 received at least 1 dose of AVE. The 6-month-PFS was 18% (95% CI 4-33) in both cohorts. At the time of analysis, 2 pts were progression-free and continuing study treatment. Median OS in cohort-1 and -2 was respectively 26 wks (95% CI 21-32) and 18 wks (95% CI 14-22). No clear relation was found between baseline cognitive functioning (Cogstate subtests) and PFS/OS. The best overall response rate (iRANO) was 41% and 26% respectively for pts in cohort-1 and -2. The most frequent all-grade treatment-related adverse events (TRAE) were dysphonia (67%), lymphopenia (50%), diarrhea (48%), hypertension (48%), and fatigue (46%). The incidence of grade 3-4 TRAE was 30%; there were no grade 5 AE. Conclusions: The combination of AVE plus AXI is sufficiently well tolerated but did not meet the threshold for activity justifying further investigation in an unselected population of patients with rGB. Clinical trial information: NCT03291314.

Early safety and efficacy from a phase I open-label clinical trial of CD137(4-1BB) agonistic antibody LVGN6051 as monotherapy and in combination with pembrolizumab.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2521-2521
Author(s):  
Siqing Fu ◽  
Wael A. Harb ◽  
Sapna Pradyuman Patel ◽  
Charles Lu ◽  
Daniel M. Halperin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Safety Profile ◽  
Single Agent ◽  
Human Study ◽  
Hepatic Metastases ◽  
Preliminary Evidence ◽  
Open Label ◽  
Grade 3 ◽  
Favorable Safety

2521 Background: LVGN6051, a monoclonal antibody against CD137 (also known as 4-1BB or TNFRSF9) with an engineered Fc capable of selectively binding to the Fcγ receptor IIB, acts as a conditional CD137 agonist, resulting in immune activation optimally in tumor microenvironment ( Qi, Nat. Commun. 2019 ). In preclinical models, LVGN6051 demonstrated robust anti-tumor efficacy and safety as a single agent and in combination with anti-PD-1 antibodies. Therefore, we have initiated this first-in-human study of LVGN6051 alone or in combination with pembrolizumab for the treatment of advanced or metastatic malignancy. Methods: This study includes accelerated dose escalation monotherapy up to 2 mg/kg of LVGN6051, and traditional 3 + 3 design for higher doses of LVGN6051 alone or in combination with pembrolizumab. Then, this study will enroll patients with specific types of malignancies following Simon’s two-stage design. Both agents are administered once every 3 weeks. Primary objectives of this study were to define the safety profile and to establish the recommended phase 2 dose (RP2D) of LVGN6051 alone or in combination with pembrolizumab. Pharmacokinetics, immunogenicity, pharmacodynamics and clinical efficacy will be also evaluated. Results: At the cut-off date on January 18, 2021, 16 subjects have been enrolled into the monotherapy cohorts (n=12, no DLT observed up to 7 mg/kg), and the combination cohort (n=4, ongoing at LVGN6051 2 mg/kg and pembrolizumab 200 mg, one DLT observed). No treatment-related adverse event (TRAE) was observed in monotherapy. Treatment-emergent adverse events (TEAE) in combination included increased ALT/AST, thrombocytopenia, and fatigue. In the combination cohort, one patient with predominant hepatic metastases and history of intermittent grade 2 hepatic impairment experienced grade 3 increased ALT/AST (DLT) on cycle 1 day 15 that were resolved to her baseline without corticosteroids on cycle 1 day 18. TRAE included increased ALT/AST, thrombocytopenia, neutropenia, nausea and fatigue. Seven of 10 evaluable patients in the monotherapy cohorts demonstrated stable disease with the longest treatment being 8+ months. Tumor reductions by >10% were observed in melanoma and neuroendocrine tumor on monotherapy. One patient with metastatic head and neck squamous cell carcinoma who had progressed on an anti-PD-L1 based therapy showed an immune partial response (iPR) for 6+ months to the combination therapy. Conclusions: Preliminary evidence showed that LVGN6051 was well tolerated and tumor shrinkages were observed. While we continue assessing its safety profile, antitumor activity was observed in the LVGN6051 and pembrolizumab cohort. The favorable safety profile and preliminary antitumor activity warrant further evaluation in patients with advanced malignancies. Clinical trial information: NCT04130542.

Inducible T-cell co-stimulatory (ICOS) receptor agonist, feladilimab (fela), alone and in combination (combo) with pembrolizumab (P): Results from INDUCE-1 urothelial carcinoma (UC) expansion cohorts (ECs).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4519-4519
Author(s):  
Arjun Vasant Balar ◽  
Victor Moreno ◽  
Eric Angevin ◽  
Hui Kong Gan ◽  
Maria Vieito ◽  
...  
Keyword(s):  
T Cell ◽  
Single Agent ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Metastatic Setting ◽  
Duration Of Response ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Tumor Types

4519 Background: INDUCE-1 is a first-in-human trial evaluating fela, an IgG4 ICOS agonist non-T-cell depleting mAb, as monotherapy (mono) and in combo with P. ECs include tumor types, such as UC, with high ICOS expression and immunotherapy-favorable features. Fela induced IFNγ, increased PD-1/L1 expression, and enhanced antitumor activity in combo with PD-1 blockade nonclinically. We report preliminary efficacy, safety, and biomarker data of fela ± P in INDUCE-1 UC ECs. Methods: Eligible patients (pts) had recurrent/metastatic (R/M) UC of the upper or lower urinary tract, ≤6 prior systemic therapy lines in the advanced setting, measurable disease, and no active autoimmune disease. Pts received 0.3 or 1 mg/kg fela (mono EC; anti-PD-1/L1–experienced [exp] pts) or 0.3 mg/kg fela + 200 mg P (combo EC; anti-PD-1/L1–naïve pts) every 3 wks, up to 35 cycles until disease progression or unacceptable toxicity. Disease was assessed every 9 wks through wk 54, then every 12 wks. Archival and/or fresh biopsy tumor tissue was collected for biomarker analyses and safety assessed. Results: By Nov 6 2020, 13 anti-PD-1/L1–exp and 32 anti-PD-1/L1–naïve pts were evaluable in the mono and combo ECs, respectively. In the mono EC, median age was 69 yrs (range: 47–82), 92% of pts were male, and 85% received ≥2 prior therapy lines in the metastatic setting. In the combo EC, median age was 70 yrs (range: 42–84), 75% of pts were male, and 72% received ≥1 prior therapy line in the metastatic setting. In the mono EC, median duration of follow-up (mDoF) was 10.6 mo (range: 1.1–22.8); overall response rate (ORR) was 8% (1 partial response [PR]; 95% CI: 0.2, 36.0) with a duration of response (DoR) of 6.1 mo; disease control rate (DCR [response or stable disease for ≥9 wks]) was 23% (95% CI: 5.0, 53.8), and median overall survival (mOS) was 14.5 mo (95% CI: 2.8, NR), with 74% of pts alive at 6 mo. In the combo EC, mDoF was 9.6 mo (range: 0.9–28.3); ORR was 22% (7 PRs; 95% CI: 9.3, 40.0) with a median DoR of 8.3 months (range: 3.5–23.3+); DCR was 63% (95% CI: 43.7, 78.9), and mOS was 10.7 mo (95% CI: 5.2, 18.1), with 64% of pts alive at 6 mo. Grade ≥3 treatment-related AEs were reported for 0% and 9% of pts in the mono (N = 16) and combo (N = 44) safety populations, respectively. PD-L1 expression and ICOS-specific biomarkers are being evaluated, with promising trends observed in enrichment of clinical activity in preliminary analyses. Conclusions: Fela is the first ICOS agonist with reported single-agent activity in anti-PD-1/L1–exp relapsed/refractory UC. Fela + P in combo shows promising clinical activity and manageable safety in PD-1/L1–naïve R/M UC. Further study is warranted. Updated data to be presented. Funding: Study 204691 (NCT02723955) funded by GlaxoSmithKline in collaboration with Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA. Clinical trial information: NCT02723955.

Activity of cabozantinib (XL184) in metastatic melanoma: Results from a phase II randomized discontinuation trial (RDT).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8531-8531 ◽  
Author(s):  
Michael S. Gordon ◽  
Harriet M. Kluger ◽  
Geoffrey Shapiro ◽  
Razelle Kurzrock ◽  
Gerald Edelman ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Braf Mutation ◽  
Tumor Regression ◽  
Progression Free Survival ◽  
Bone Lesions ◽  
Open Label ◽  
Grade 5 ◽  
Common Grade ◽  
Grade 3 ◽  
Tumor Types

8531 Background: MET and VEGF signaling are implicated in angiogenesis, invasion, and metastasis. Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. A RDT evaluated activity and safety in 9 tumor types. Here we report on the metastatic melanoma cohort, including the ocular subtype. Methods: Eligible patients (pts) were required to have progressive measurable disease per RECIST. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Primary endpoint in the randomized phase was progression free survival (PFS). Results: Enrollment to this cohort is complete (n = 77); all pts are unblinded. Baseline characteristics: median age 66 years; melanoma subtype: cutaneous/mucosal 70% and ocular 30%; known BRAF mutation 32%; LDH ≥ 1.1 x upper limit normal 35%; bone metastases 19%; median prior lines of therapy 1 (range 0-5). Median follow-up was 2.8 months (range 0.3 - 25). 35 pts (45%) completed the open-label Lead-in stage with 25 pts randomized to continue cabo (n=12) or to placebo (n=13). Median PFS from randomization was 5.7 months for cabo vs. 3 months for placebo (HR=0.3, p =0.055). Median PFS from Study Day 1 was 4.4 months. The estimate of PFS at month 6 (PFS6) is 44%. Evidence of objective tumor regression was observed in 39/65 pts (60%) with ≥ 1 post-baseline tumor assessment including 11/23 pts (48%) with ocular melanoma. Two bone scan evaluable pts demonstrated partial resolution of bone lesions at wk 6 accompanied by pain relief. Most common Grade 3/4 AEs were fatigue (14%), HTN (9%), constipation (4%), and diarrhea (3%); one related Grade 5 AE of diverticular perforation and peritonitis reported during Lead-in stage. Conclusions: Cabo demonstrates activity in metastatic melanoma pts, regardless of subtypes or BRAF mutation status, with improvement in PFS relative to placebo, and high rates of PFS6 and objective tumor regression. The safety profile of cabo was comparable to that of other VEGFR TKIs.

A randomized phase II study (VEG108838) of lapatanib plus pazopanib (L+P) versus lapatanib (L) in patients with ErbB2+ inflammatory breast cancer (IBC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 531-531 ◽  
Author(s):  
Massimo Cristofanilli ◽  
Stephen R. D. Johnston ◽  
Alexey Manikhas ◽  
Henry Leonidas Gomez ◽  
Oleg Gladkov ◽  
...  
Keyword(s):  
Randomized Study ◽  
Single Agent ◽  
Clinical Activity ◽  
Study Cohort ◽  
Open Label ◽  
Double Blind ◽  
Meaningful Improvement ◽  
Grade 3 ◽  
To Receive ◽  
Dose Reductions

531 Background: ErbB2 amplification is frequently reported in IBC and there is evidence of positive association between ErbB2 and VEGF expression. We evaluated the combination of anti ErbB2 and VEGF therapy in ErbB2+ IBC. Methods: We conducted a multicenter, randomized clinical trial for patients (pts) with relapsed ErbB2+ IBC. Cohort 1: Pts stratified (prior trastuzumab; cutaneous disease only vs systemic) and randomized 1:1 to receive L 1500 mg + placebo or L 1500 mg + P 800 mg, QD. Due to high incidence of Grade 3/4 diarrhea in pts treated with L 1500 mg+ P 800 mg in another study, Cohort 1 was closed after 76 pts randomized. Cohort 2 (87 pts ): Pts were stratified (prior trastuzumab) and randomized 5:5:2 to receive L 1500 mg + placebo or L 1000 mg + P 400 mg (double-blind) or P 800 mg (open-label), respectively, QD. Treatment continued until PD, unacceptable toxicity or death. Primary endpoint was ORR. Secondary endpoints included PFS, OS, and safety. Results: Cohort 1: 76 pts were randomized and treated: L, n=38; L+P, n=38. ORR was 29% for the L arm, and 45% for the L+P arm. Median PFS was 16.1 and 14.3 wks, respectively, for the L and L+P arms. The most frequent Grade ≥3 AEs were diarrhea (0% vs 18%) vomiting (0% vs 8%), ALT increased (0% vs 8%), neutropenia (3% vs 13%), and bilirubin increased (0% vs 5%). Dose reductions due to AE were 3% and 21% and dose interruptions due to AE were 11% and 55% in the L and L+P arms, respectively. Cohort 2: 88 pts were randomized (87 treated): L, n=36; P, n=14; L+P, n=38. The ORR was 47%, 31%, and 58% for the L, P, and L+P arms, respectively. Median PFS was 16.0, 11.4, and 16.0 wks for the L, P, and L+P arms, respectively. The most frequent Grade ≥3 AEs were ALT increased (0%, 0%, 21%), AST increased (0%, 0%, 18%), diarrhea (3%, 8%, 8%), and fatigue (3%, 8%, 8%). Dose reductions due to AE occurred in 0%, 0%, and 13% of pts and dose interruptions due to AE occurred in 22%, 23%, and 39% of pts in the L, P, and L+P arms, respectively. Conclusions: This prospective, randomized study confirmed the clinical activity of lapatinib single agent in metastatic ErbB2+ IBC. Furthermore, we demonstrated increased toxicity associated with the combination without a clinically meaningful improvement in efficacy.

Phase 1-2 study of progesterone receptor (PR) inhibition with extended-release (ER) onapristone (ONA) alone or in combination with abiraterone (AA) in patients (pts) with castration-resistant prostate cancer (CRPC) incorporating plasma DNA analysis to define androgen receptor (AR) status.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5071-5071
Author(s):  
Anuradha Jayaram ◽  
Karolina Nowakowska ◽  
Joaquin Mateo ◽  
Sanjeev Kumar ◽  
Tatiana Hernandez ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dna Analysis ◽  
Phase 1 ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Clinical Activity ◽  
Type I ◽  
Castration Resistant Prostate Cancer ◽  
Plasma Dna ◽  
Open Label

5071 Background: An urgent need exists for new therapies after progression (PD) onAA and enzalutamide (ENZ). Increased PR expression or progesterone-activating AR mutations have been associated with resistance to AR targeting. We aimed to test ONA, a type I PR antagonist with clinical activity in PRpos cancers, in AA/enz-resistant CRPC. In a prospectively defined exploratory analysis, we aimed to report outcome by plasma AR status ( pAR). Methods: This was a multi-institution, open label phase I/II clinical trial in pts progressing after ENZ/AA. Pts were first treated with single agent (SA) ONA using a randomised dose escalation design. ONA at 2 doses was then combined with AA (1000mg od with pred 5mg bid) in pts progressing on AA. The primary end-points were safety, pharmacokinetics (PK) and anti-tumor activity split by p AR. Archival and metastatic biopsies were collected when possible and tested for PR status. p AR was studied using previous methods (Romanel STM 2015). Results: 21 pts received SA ONA (5 = 10mg/ 5 = 20mg/ 4 = 30mg/ 4 = 40mg /3 = 50mg BID) and 15 pts received ONA-AA combination (5 = 30mg ONA BID, 10 = 50mg ONA BID). There were not DLTs or significant LFT abnormalities and no G3/4 adverse events (AE), no treatment discontinuations due to AEs and no SAEs considered related to ONA. PK in SA ONA observed active plasma concentrations and no interaction with AA. Of 32 evaluated pts 15 had a 2105T > A (p.L702H) or 2632A > G (p.T878A) AR mutation detected in plasma pre-treatment and 1 had AR copy number gain. PSA declines were not observed with SA ONA but in 2 pts with combination (-30%, -7%) who were AR normal. The rPFS on SA ONA was 2.8 months for AR normal and 2.6 for AR aberrant (Hazard ratio (HR) 1.41; 95% CI, 0.62-3.72; P 0.48) and on combination was 4.4 months for AR normal (8/15) and 2.2 for AR aberrant (7/15) (HR 6.08; 95%CI, 6.32-221.9; P < 0.001). Conclusions: ONA is safe in CRPC as SA and in combination with AA. There was no difference in rPFS by p AR status for SA ONA but on the combination with AA, pts who were plasma AR normal had a significantly longer rPFS. Clinical trial information: NCT02049190.

An open label, single-arm, two-stage, multicenter, phase II study to evaluate the efficacy and safety of TLC388 as second-line treatment in subjects with poorly differentiated neuroendocrine carcinomas (TCOGT1Z14).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4101-4101
Author(s):  
Ming-Huang Chen ◽  
Wen-Chi Chou ◽  
Chin-Fu Hsiao ◽  
Yi-Chang Liu ◽  
Chiun Hsu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Biological Behavior ◽  
Open Label ◽  
Poorly Differentiated Neuroendocrine Carcinoma ◽  
Platinum Based Chemotherapy ◽  
Camptothecin Analogs ◽  
Phase 2 Clinical Trial ◽  
Poorly Differentiated ◽  
Prior Systemic Therapy ◽  
Grade 3

4101 Background: Therapeutic options for metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum‐based chemotherapy are unknown. Camptothecin analogs, like topotecan and irinotecan, are approved chemotherapy in small cell lung cancer (SCLC). NEC is considered to have similar biological behavior to SCLC. The aim of this study was to analyze the efficacy of TLC388 (Lipotecan) Hydrochloride, which is a novel camptothecin analog, in pretreated metastatic NEC patients. Methods: This single-arm, 2-stage, phase 2 clinical trial was conducted at 4 community and academic centers in Taiwan. Patients aged 20 years or older enrolled between July 2015 to May 2018 had confirmed metastatic NEC with prior systemic therapy with etoposide plus cisplatin. Patients received intravenous 40 mg/m2 of TLC388 on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxic effects. Results: twenty-three patients with a median age of 61 (range, 44-73) years, including 18 men (78%), were enrolled. Patients received a median of 2 (range, 0-6) treatment cycles. Among 20 evaluable patients, three patients showed a stable disease and no patient a complete or partial remission, resulting in a disease control rate of 15%. Median PFS was 1.8 (95% CI, 0.4-15) months and median OS was 4.3 (95% CI, 1.7-15) months. The most common treatment-related hematologic adverse events at grade 3 or higher were leukopenia (22.7%), anemia (31.8%), and thrombocytopenia (18.2%), respectively. Conclusions: TLC388 shows modest antitumor activity in metastatic NEC. Clinical trial information: NCT02457273.

A phase II clinical trial of ipilimumab/nivolumab combination immunotherapy in patients with rare upper gastrointestinal, neuroendocrine, and gynecological malignancies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2570-2570 ◽  
Author(s):  
Oliver Klein ◽  
Damien Kee ◽  
Ben Markman ◽  
Rachael Chang Lee ◽  
Michael Michael ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Combination Treatment ◽  
Single Agent ◽  
Low Frequency ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Wide Range ◽  
Grade 3 ◽  
Upper Gastrointestinal

2570 Background: Patients (pts) with rare cancers represent an unmet medical need and have an inferior overall survival compared to patients with more common malignancies. Due to their low frequency, no therapies, including immunotherapies, have systematically been investigated in this population. Ipilimumab (ipi)/Nivolumab (nivo) combination treatment has demonstrated significant clinical activity in pts with advanced melanoma and renal cell carcinoma and response rates with this regimen are higher compared to single agent anti-PD-1 therapy. This phase II study assessed the efficacy and safety of ipi/nivo in rare cancer pts. Methods: 60 pts with advanced rare upper gastrointestinal (GI), neuroendocrine (NE) and gynaecological (GY) malignancies were enrolled in 3 cohorts. Patients received nivo 3mg/kg and ipi 1mg/kg every 3 weeks for four doses, followed by nivo 3mg/kg every 2 weeks. Treatment continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR), CR, PR and SD. Exploratory endpoints include correlation of efficacy with relevant biomarkers including PDL1 status and tumour mutation burden. Results: 42 pts have so far undergone restaging, 11 pts clinically progressed prior to their first restaging scan. 50 pts have received prior therapy (1-5 lines). Objective responses have been observed in a range of different malignancies. Clinical trial information: NCT02923934. Grade 3/4 immune related adverse events were detected in 31% of pts. The results of correlative biomarker studies will be presented at the meeting. Conclusions: Ipi/Nivo combination treatment has efficacy in a wide range of advanced rare malignancies. Immune related toxicity is in keeping with previously reported clinical trials using the same dosing regimen.[Table: see text]

scholarly journals ACTR-26. SAFETY AND EFFICACY OF BEVACIZUMAB PLUS TTFIELDS IN PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM): DATA FROM A PHASE II CLINICAL TRIAL

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi18-vi18 ◽  
Author(s):  
Jaleh Fallah ◽  
Rekha Chaudhary ◽  
Lisa Rogers ◽  
Wei (Auston) Wei ◽  
Cathy Brewer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Disease Progression ◽  
Muscle Weakness ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Open Label ◽  
Safety And Efficacy ◽  
Phase 2 Clinical Trial ◽  
Recurrent Gbm

Abstract BACKGROUND Studies of bevacizumab monotherapy and TTFields monotherapy have shown activity but limited clinical benefit in patients with recurrent GBM. In an open label, single-arm, phase 2 clinical trial, the safety and efficacy of the combination of bevacizumab and TTFields was studied in patients with recurrent GBM. METHOD Bevacizumab-naïve patients with histologically confirmed GBM or other grade IV glioma, with recurrent disease after radiotherapy and temozolomide chemotherapy, were eligible. Bevacizumab dose was 10mg/kg intravenously every 2 weeks and TTFields was worn at least 18 hours daily. The primary endpoint was safety, progression-free survival at 6 months (PFS6) and overall survival at 12 months (OS12). Treatment was continued until disease progression or unacceptable toxicity. Survival outcomes were assessed using the Kaplan-Meier method. Treatment-related adverse events were reported according to CTCAE, v4.0 criteria. RESULTS 25 patients were enrolled and 23 were eligible for data analysis: 18 (78%) men and 5 (22%) women, median age 60 years (range 17–78). 21 patients were Caucasian, 1 was African American and 1 of unknown race. Median follow-up was 6.0 months (range 2.4–22). Seven patients (30 %) had disease progression. Median PFS was 9.9 (95% CI: 6.7-NA) months. PFS rate at 6 months (PFS6) was 71% (95% CI: 0.54–0.94). Median overall survival was 9.9 (95%CI 7.3-NA) months. OS rate at 12 months (OS12) was 42% (95%CI 0.24–0.74). 7 patients (30%) had grade 3 toxicity (cough, dysphagia, muscle weakness, hyperglycemia, hypertension, psychosis, seizure, lymphopenia, transaminitis). 1 patient developed grade 4 muscle weakness in the lower extremities. CONCLUSION Treatment with the combination of bevacizumab and TTFields in patients with recurrent GBM is safe and feasible and has shown clinical efficacy.

A Phase I Study of Vorinostat in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3705-3705 ◽  
Author(s):  
David Siegel ◽  
Donna Weber ◽  
Constantine S. Mitsiades ◽  
Syed Rizvi ◽  
Jose Garcia-Vargas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Progressive Disease ◽  
Therapeutic Potential ◽  
Hematologic Malignancy ◽  
Randomized Study ◽  
Single Agent ◽  
Clinical Activity ◽  
Open Label ◽  
Tumor Types

Abstract Introduction: Multiple myeloma (MM) is the second most common hematologic malignancy after non-Hodgkin’s lymphoma and despite recent advances in therapy, including the introduction of thalidomide, bortezomib, and lenalidomide, remains incurable. Vorinostat is an inhibitor of Class I and II histone deacetylases, which play key roles in the regulation of both transcriptional and post-transcriptional activity in a variety of tumor types, including MM. This histone deacetylase inhibitor has demonstrated anti-proliferative activity as monotherapy and synergistically with other agents in a variety of tumor types, including MM, where it was well tolerated in Phase I trials. Lenalidomide is a potent structural analog of thalidomide and demonstrates clinical efficacy in the treatment of MM as a single agent and to a larger degree, in combination with dexamethasone. Preclinical data suggest that the addition of vorinostat to lenalidomide and dexamethasone has at least additive, and possibly synergistic, therapeutic potential, with the anti-tumor mechanisms of vorinostat and dexamethasone being distinct from the immunomodulatory effects of lenalidomide. This Phase I, multicenter, open-label, non-randomized study assessed the safety and tolerability of vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory MM. Methods: The primary objective was to determine the maximum tolerated dose (MTD). Secondary and exploratory objectives included: assessment of safety and tolerability; determination of clinical activity of the combination, and evaluation of in vivo molecular and biologic effects of the combination in patients with MM through analysis of gene expression. Patients aged ≥18 years with an established diagnosis of relapsed or refractory MM were enrolled sequentially into 1 of 5 dosing levels (table). Patients received vorinostat daily, administered orally for 14 days with 7 days on (Days 1–7 and 15–21), combined with oral lenalidomide daily for 21 days, and oral dexamethasone 40 mg/day (Days 1, 8, 15, and 22; cycles were repeated every 28 days); use of concomitant prophylactic acetylsalicylic acid was recommended. Dose-limiting toxicities (DLTs) were assessed in the first treatment cycle. Barring DLT, dose escalation continued until the MTD was established. Response, safety, and tolerability were evaluated. Adverse events (AEs) were recorded throughout the study. Dosing Regimen Dose Level Vorinostat Dose (mg q.d.) 7 days on 7 days off (Days 1–7 and Days 15–21) in each 28-day cycle Lenalidomide Dose (mg q.d.) × 21 days (Day 1 through Day 21) in each 28-day cycle Dexamethasone Dose (mg q.d.) On Days 1, 8, 15, and 22 in each 28-day cycle 1 300 10 40 2 400 10 40 3 400 15 40 4 400 20 40 5 400 25 40 Results: Enrolment is ongoing and tolerability of treatment has been good so far. Of 7 patients assessed to date, 6 patients (86%) have reported ≥1 AE, and 3 patients’ (43%) AEs were considered drug-related. The most frequently reported AE was anemia (n=4, 57%). Serious AEs were reported by 2 patients (29%), none of which were considered drugrelated. No patients have discontinued due to AEs or SAEs, and no DLT has been observed to date. Of 6 evaluable patients, the best responses were: partial response in 1 patient, minimal response in 1 patient and stable disease in 2 patients and progressive disease in 2 patients. Currently, 4 patients remain on treatment and 3 patients have discontinued treatment due to progressive disease. Conclusion: Vorinostat with lenalidomide and dexamethasone represents a novel combination therapy for the treatment of relapsed or relapsed, refractory MM. Preliminary results suggest that the combination is well tolerated to date, is active and has the convenience of oral administration.

Phase IIa trial of cilengitide (EMD121974) single-agent therapy in patients (pts) with recurrent glioblastoma (GBM): EMD 121974-009

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2002-2002 ◽  
Author(s):  
D. Reardon ◽  
K. Fink ◽  
B. Nabors ◽  
T. Cloughesy ◽  
S. Plotkin ◽  
...  
Keyword(s):  
Karnofsky Performance Status ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Median Number ◽  
Recurrent Glioblastoma ◽  
Tumor Control ◽  
Clinical Activity ◽  
Open Label ◽  
Recurrent Gbm

2002 Background: Our phase IIa study evaluated the safety, toxicity, and clinical activity of the cyclic RGD pentapeptide cilengitide (EMD121974), an inhibitor of integrins avβ3 and avβ5, as a single agent at doses of 500 and 2000 mg in pts with recurrent GBM. Methods: In this multicenter, open-label, randomized, uncontrolled study, pts with GBM and measurable disease that had relapsed after previous temozolomide and radiotherapy were randomized to receive cilengitide at either 500 mg or 2000 mg i.v., 2x/week, until progression. Neurologic exams were performed after every cycle (4 weeks) and MRIs were performed every other cycle. Central, blinded pathology and radiology reviews were performed. The primary endpoint was Progression Free Survival (PFS) at 6 months (6-mth PFS). Secondary endpoints included response, survival, time to disease progression, safety, tolerability and pharmacokinetics (PK). Results: 81 pts accrued (median Karnofsky Performance Status 80%; median age 57 yrs) at 15 sites including 41 at the 500 mg and 40 at the 2000 mg dose levels. Demographic and pretreatment variables were comparable between dose level cohorts. The median number of infusions was 16 [range, 4–179]. PK studies revealed significantly greater exposures among the 2000 mg cohort. Treatment related NCI CTC grade 3 adverse events (AEs) included elevated transaminases (at 500 mg), arthralgia/ myalgia (at 500 mg), and weight increase/ edema (at 2000 mg) in 1 patient, respectively. No grade 4 therapy related AEs were reported. One CTC grade 2 cerebral hemorrhage was reported in a pt at progression. The 6- mth PFS was 16.1% (n=13/81 pts). 10 pts (12.3 %, n=4 with 500 mg, n=6 with 2000 mg) received 12 or more cycles. Six pts (7.4%) remain progression-free and on treatment. Median Overall Survival (mOS) was 6.5 mths [95% CI: 5.2–9.3 mths] in the 500 mg arm and 9.9 mths [95% CI, 6.3–15.7 mths] in the 2000 mg arm. Although not statistically significant, there was a trend towards better tumor control in pts receiving 2000 mg 2x/week. Conclusions: Cilengitide was well tolerated and demonstrated single agent activity in recurrent GBM, with long term disease stabilization in a subset of pts. [Table: see text]

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